The overall goal of this project is to study the effects of specific diabetes susceptibility genes on insulin secretion and to define clinical protocols which describe the altered pattern of secretion associated with expression of these genes. Since susceptibility genes for the common form of late-onset NIDDM have not yet been identified, MODY will be used as an experimental model. Three genetic subtypes of this condition (MODY1, MODY2, and MODY 3) have been identified each being linked to a separate susceptibility locus. Studies will be performed in subjects with the three forms of MODY to further define the insulin secretory responses to glucose and non-glucose stimuli on physiological testing. A specific attempt will be made to determine whether defects in insulin secretion are present in subjects genetically predisposed to MODY prior to the onset of overt hyperglycemia. Complementary studies will be performed in a mouse model in which one allele of the glucokinase gene has been knocked out. Heterozygous animals have reduced expression of glucokinase in the B-cell and liver and in this respect resemble subjects with MODY2 in which the mutation in the enzyme glucokinase results in production of an inactive enzyme. Using the isolated perifused pancreas and isolated perfused islets we propose to study responses to non-glucose stimuli in these animals, alterations in oscillatory insulin secretion and the ability of animals lacking one glucokinase allele to compensate for mild hyperglycemia and insulin resistance. It is proposed to explore the mechanisms associated with altered insulin secretion in subjects with impaired glucose tolerance by determining if they are reversible by treatment with metformin, a biguanide which lowers glucose levels by suppressing hepatic glucose production and troglitazone, a novel agent which appears to reduce peripheral insulin resistance. We will also determine whether subjects with impaired glucose tolerance are able to increase insulin secretion in response to infusion of a triglyceride emulsion and heparin, a combination which increases insulin resistance by increasing the concentrations of free fatty acids. It is anticipated that these studies will provide mechanistic insights into the role of abnormal B-cell function in the pathophysiology of NIDDM. By allowing the manifestations of the insulin secretory defects present in subjects with impaired glucose tolerance to be compared with those present in MODY, these studies should define experimental approaches which will uncover B-cell dysfunction at an early stage in the development of NIDDM even before the onset of overt hyperglycemia.